There exists clinical and scientific evidence for excitatory and inhibitory processes which contribute to excitable system activity, pain and psychiatric disorders. The pharmacologic actions of analgesic and anti-depressant agents prescribed to counteract these disorders are thought to be elicited through interactions with endogenous receptors which alter the activity of excitable systems.
Excitable System Disorders
Clinical depression is characterized by symptoms which include failure to obtain pleasure from activities which previously brought enjoyment. Similarly, individuals experiencing difficulties with alcohol, tobacco, stimulants such as cocaine and narcotic analgesics such as heroin, have a depressive syndrome characterized by one or more of a poor self image, feelings of incompetence and/or inadequacies, alienation, unpopularity and the like. The pathologic feelings of these depressed and/or drug dependent individuals have been collectively called "hypophoria," and are manifest by a general loss of pleasure and interest in most typical activities. Such hypophoric feelings are an essential feature of the persistent depressive state as described by the American Psychiatric Association.
These same hypophoric feelings are also present in many adolescents and are particularly strong in those that have been diagnosed as having conduct disorders. Moreover, it is well established that adolescence and early adulthood is a turbulent time in development when drug abuse, mood and behavior problems emerge. Thus, the lack of coping skills needed to cope with emerging needs in a socially acceptable manner and the ability of psychoactive drugs to decrease the associated discomfort have long been considered related.
Most drugs of abuse, at least on a temporary basis, reverse depressive or hypophoric feelings--an attribute that is, at least in part, thought to be responsible for their reinforcing effects. For heroin, morphine and related drugs, barbiturates, amphetamine, cocaine and marijuana, this role for the anti-hypophoric effect has been unequivocally demonstrated.
When individuals use opioid drugs such as heroin, morphine and the like, they soon become dependent and, upon withdrawal, an abstinence syndrome emerges. Typically, such a syndrome is initially quite discomforting and in many ways resembles a severe flu-like illness, including chills, fever, heightened autonomic tone, and decreased caloric intake. This is followed by a chronic illness characterized by exaggerated responsiveness to stressful and painful stimuli and lessened tone of the autonomic nervous system. This latter phase has been called protracted or secondary abstinence.
Associated with this increased responsiveness to pain are exaggerated feelings of tiredness, lack of energy and social withdrawal, as well as hypophoria. These symptoms are also common to many mood and behavior disorders. Thus, a cycle traps drug abusers and those individuals with mood and behavior disorders in a deepening condition of discontent and hypophoria with a state of continuing vulnerability.
Several studies concerned with the psychiatric profiles of cocaine users have indicated that these patients may exhibit a range of other psychiatric disorders including depression, bipolar disorder, cyclothymia and attention deficit disorders. Further, a variety of drugs of abuse, including morphine-like drugs, amphetamines and barbiturates, produce dose related increases on the Morphine-Benzedrine Group (MBG) scale which measures feelings of well being and contains items which are polarly opposite to the items comprising the hypophoria scale of the Addiction Research Center Maturation Scale (ARCMS). Cocaine's subjective effects are very similar to the effects of amphetamines.
These findings support the hypothesis that many substance abusers have a depressive diathesis and that drugs of abuse provide at least temporary relief from these pre-existing psychopathologies. However, drugs of abuse may worsen pre-existing psychopathologies and therefore further predispose individuals to diseases of pharmacologic adaptation and addiction.
Although the efficacies of currently available anti-depressant preparations are established, a number of prominent problems exist with therapeutic use of these agents. For example, biological heterogeneity of even the most carefully diagnosed patients with depressive diatheses is a fundamental problem facing clinicians. Moreover, less than satisfactory efficacy is a problem in a portion of this patient population, and nearly all of the available anti-depressants have deleterious side effects which are attributable to a lack of specificity, and/or cross-reactivity with regard to endogenous central nervous system processes.
There is thus a need in the art for therapies to effectively treat psychopathologies, including, pain, hypophoria, drug abuse, depression, and the like, that are the result of excitable system disorders and abnormalities.
2. Varied and Paradoxical Response to Psychoactive Drugs
There is wide heterogeneity of patients and their responses to psychoactive drugs used to treat pain and psychiatric diatheses. Patients suffering with chronic pain are often predisposed to depressive states which result in disruption of lifestyle and frequently to use and abuse of drugs.
Research in the past has implicated several chemically and functionally different excitable system neurochemical-receptor systems in central analgesic processes which are evocable and relieve certain painful conditions (i.e., nicotinic and muscarinic cholinergic, catecholamine, serotonin, enkephalins, dynorphins, NMDA and nitric oxide).
Available scientific literature concerned with these processes involved with one of the primary results of excitable system activity disorders, "pain," can be summarized as follows: First, there is duality of function (i.e., excitation vs. inhibition, analgesia and hyperalgesia, etc.) in every system; Second, there is redundancy of location and function for each system; Third, there is within and between systems modulation of function; and Fourth, there appears to be both within and between species variation in the duality and redundancy of function.
Opioid and nicotinic cholinergic excitation processes have been demonstrated in the pontomedullary and mesencephalic reticular systems of dog and rat.
There appears to be tonic activity of these processes since opioid and nicotinic antagonists (e.g., naltrexone and mecamylamine) produce dose related analgesia when injected into active excitatory sites. There is, however, a high degree of individuality in the activity of these processes as well as in response to antagonists of central neurohumors.
Different populations of inhibitory or facilitatory neurons have also been demonstrated in ventral portions of the brain stem which are involved in analgesic responses to a number of narcotic analgesics. Other investigations have identified spinal opioid "anti-analgesic" processes which involve dynorphin. In addition, both excitatory and inhibitory opioid activity in dorsal root ganglion cell cultures that are associated with changes in regulatory G-protein function have been detected. These studies have all demonstrated the excitatory action of classical opioids such as morphine, as well as an anti-excitatory action of opioid antagonists.
Clinical studies, on the other hand, have reported paradoxical effects of opioid agonists and antagonists. For example, naloxone has been reported to produce both analgesia and hyperalgesia in man. Naloxone also has the ability to both suppress and enhance the response to nociceptive stimuli in animals. In addition, nalaxone enhancement of the analgesic action of nitrous oxide has led to the postulation of an existence of both analgesic and hyperalgesic systems (i.e., duality) in the brain.
With respect to morphine and nicotine, high doses of morphine administered intrathecally produce hyperalgesia in both man and animals, and a number of investigators have shown that nicotine produces analgesia after either parenteral or central administration in a variety of species including the cat, mouse, rat, dog and man. Using muscarinic and nicotinic agonists and antagonists, it has further been demonstrated that nicotine produces analgesia through nicotinic and muscarinic cholinergic mechanisms as well as through opioidergic mechanisms. There is, thus, substantial evidence for distinct nicotinic and muscarinic components involved in the production of analgesia.
Taken together these experimental findings document the existence of excitatory and inhibitory opioid and cholinergic process in several excitable systems.
Similar to opioid and cholinergic processes involved with inhibitory and excitatory influences, the role of biogenic amines, in particular serotonin, has been extensively investigated with contradictory findings prevalent throughout the literature. Early studies using the electrical stimulation and the rat tail flick method showed no effect of methysergide on the thresholds for spinal reflex or vocalization during stimulation, but increases in vocalization after the period of stimulation. There have also been a number of studies showing no effect of systemic methysergide on the tail flick, hot plate and formalin nociceptive assays.
Similarly, hyperalgesia, analgesia or no effect have been reported following systemic administration of metergoline.
As yet other examples, increased sensitivity to nociceptive stimuli has been shown for mianserin, although negative findings have also been reported. Negative results have likewise been reported for cyproheptadine using the tail flick and hot-plate assay, but increased and decreased sensitivities to nociceptive stimuli have been demonstrated with other experimental procedures.
In a live rat model system, a serotonergic agonist (5MeODMT) which is known to cross the blood brain barrier decreased nociceptive responses in the hot plate, tail flick and shock titration assays. Yet, these effects were blocked by mianserin or metergoline only in the tail flick method. In spinalized rats, on the other hand, the opposite effects have been demonstrated.
Another serotonin agonist (8-OH-DPAT) has been shown to have no effect on nociceptive reflexes in the mouse tail flick assay, while producing hypo- or hyperalgesia in the hot plate and formalin bioassay. However, both analgesic and hyperalgesic effects of 8-OH-DPAT are observed when microinjected into the rat brain stem.
However, intrathecal serotonin has consistently been shown to produce analgesia which is blocked by methysergide and cyproheptadine and potentiated by fluoxetine in the tail flick assay but not in the hot plate assay.
Finally, classification of numerous molecular receptor sub-types for serotonin indicate both a duality (i.e., hyperalgesia vs. analgesia) and a redundancy of function.
3. Status of the Art
Rose et al. (Pharmacol. Biochem. Behav., 41: 219-226, 1991) hypothesize that excitable system agonist/antagonist combinations may be useful in the therapy of certain excitable system disorders. For example, Rose et al. hypothesize that combination therapy using nicotine/mecamylamine may be useful in the treatment of nicotine dependence and that methadone/naltrexone combined therapy might be employed in the treatment of heroin addiction.
Hamann et al. (Pharmacology Biochemistry & Behavior, 47: 197-201, 1994) teaches that at high doses, the hyperalgesic action of morphine is diminished and an analgesia was observed in rats. Additionally disclosed is that naltrexone produces analgesia that is diminished with increasing dose.
Hamann et al. (H. Pharmacol. Exp. Ther., 261: 707-715, 1992) discloses the analgesic effects of naltrexone and mecamylamine in rat brain sites exhibiting sensitivity to the hyperalgesic actions of (-)-nicotine and ethylketazocine. Both naltrexone and mecamylamine evoked dose-related analgesia when administered either intraperitoneally or by direct injection into active hyperalgesic brain stem regions. There is no teaching or suggestion of therapies in which both opioid and nicotinic antagonists, such as naltrexone and mecamylamine, are co-administered.
Hamann et al. (Pharmacology Biochemistry & Behavior, 43: 925-927, 1992) describe a dose related analgesia when lidocaine, cocaine, and bupivacaine were administered into the dorsal posterior mesencephalic tegmentum of conscious rats. There is, however, no mention of a combination therapy using opioid and nicotinic antagonists.
Rose et al. (Clinical Pharmacology and Therapeutics, July 1994) disclose the beneficial effect of mecamylamine in a combination therapy with a nicotine skin patch in the prolonged cessation of cigarette smoking.
Hamann et al. (Brain Research Bulletin, 29: 605-607, 1992) describes an apparent dose-related analgesic action of dynorphin A(1-13) antiserum when injected into the dorsal posterior mesencephalic tegmentum of conscious rats. Martin et al. (Society for Neuroscience Abstracts, 16: Abstract No. 267.7) describes the administration of 12 mecamylamine or naltrexone to Sprague Daily rats. When administered to the 4th ventricle, and mecamylamine antagonized the hyperalgesic effect of EKC and nicotine. There is again, however, no disclosure of naltrexone/mecamylamine combined therapy. Crain et al. (WO 95 03804) disclose a-method using co-administration of a bimodally acting opioid agonist and an excitatory opioid receptor antagonist for enhancing opiate analgesic potency or detoxifying an opiate addict.
In each of the above described publications, there is no suggestion to use combinations of two or more antagonists of excitable systems in the treatment of excitable system disorders. Moreover, there is no teaching or suggestion of combining opioid and nicotinic antagonists for treatment of excitable system abnormalities, particularly depression, drug abuse, and pain.
It is thus the present invention that for the first time provides methods for evaluating abnormalities in excitable system activity associated with psychopathologies and furnishes novel treatments with combinations of opioid, cholinergic, serotonergic and adrenergic antagonists. Application of excitable system activity compositions to the individuality of central nervous system processes which function in mediating and maintaining a balance in excitatory and inhibitory processes provides a new approach for the discovery of pharmacologic modalities which are devoid of abuse potential and are useful for the treatment of pain, drug abuse and underlying psychopathologies.